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Metabolic Signalling in Muscle- and Adipose-tissue Following Insulin Withdrawal and Growth Hormone Injection.

Information source: University of Aarhus
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Diabetes Mellitus Type I; Ketoacidosis

Intervention: Insulin withdrawal (Drug); Norditropin (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: University of Aarhus

Official(s) and/or principal investigator(s):
Niels Møller, MD, Study Chair, Affiliation: Aarhus University / Aarhus University Hospital
Thomas Voss, MD, Principal Investigator, Affiliation: Aarhus University / Aarhus University Hospital

Overall contact:
Thomas Voss, MD, Phone: +45 29911146, Email: tsvo@ki.au.dk


Diabetes mellitus type I (DM I) is characterized by lack of endogenous insulin and these patients are 100% dependent on insulin substitution to survive. Insulin is a potent anabolic hormone with its primary targets in the liver, the skeletal

muscle-tissue and - adipose-tissue.

Severe lack of insulin leads to elevated blood glucose levels, dehydration, electrolyte derangement, ketosis and thus eventually ketoacidosis. Insulin signalling pathways are well-known. Growth hormone (GH) is also a potent anabolic hormone, responsible for human growth and preservation of protein during fasting. GH (in concert with lack of insulin) induces lipolysis during fasting. It is not known how GH exerts its lipolytic actions. The aim is to define insulin and growth hormone (GH) signalling pathways in 3 different states in patients with DM I. And to test whether ATGL-related lipolysis in adipose tissue contributes to the development of ketosis. 1. Good glycemic control 2. Lack of insulin (ketosis/ketoacidosis) 3. Good glycemic control and GH injection

Clinical Details

Official title: Metabolic Signalling in Muscle- and Adipose Tissue Following Insulin Withdrawal and Growth Hormone Injection in Type I Diabetes Mellitus, a Clinical Experimental Study.

Study design: Allocation: Randomized, Intervention Model: Factorial Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science

Primary outcome: Insulin and growth hormone signalling, expressed as CHANGE in phosphorylation of intracellular target proteins and CHANGE in mRNA expression of target genes in muscle- and fat-tissue.

Secondary outcome:

Change in Intracellular markers of lipid metabolism in muscle- and fat tissue biopsies.



Detailed description: Diabetes mellitus type I (DMI ) is characterized by lack of endogenous insulin and these patients are 100% dependent on insulin substitution to survive.

Insulin is a potent anabolic hormone with its primary targets in- the liver, - the skeletal

muscle-tissue and - fat-tissue.

In the liver it enhances glycogenesis and inhibits glycogenolysis and gluconeogenesis. In skeletal muscle-tissue, it enhances glucose transport into the cell, glycogenesis, glycolysis, glucose oxidation and protein synthesis. In fat-tissue, it inhibits lipolysis and enhances lipogenesis. This indicates that a fall in serum insulin levels lead to increased blood glucose and

increased levels of FFA's (free fatty acids) in the blood - eventually leading to ketone

production. If this condition is not corrected, it will lead to ketoacidosis, which is a potentially life-threatening condition, that is to be corrected under hospital admission with fluid-therapy, electrolyte- and insulin-substitution. Insulin has been studied thoroughly and signalling pathways are well known. An interesting pathway is suppression of lipolysis. The most important and rate-limiting lipase in triglyceride hydrolysis is adipose triglyceride lipase (ATGL)(1-5). A connection between ATGL and G0/G1 switch gene (G0S2) has been shown (6,7). During lipolysis ATGL is up-regulated and G0S2 is down-regulated and the promoter region for G0S2 has binding-sites for glucose, insulin dependent transcription factors and peroxisome proliferator-activated receptors y (PPAR-y)(8). One former study has shown that fasting reduces G0S2 and increases ATGL in humane adipose-tissue(7). The anti-lipolytic effects of insulin, could be thought, to be mediated through increased transcription of G0S2 which then in turn inhibits ATGL. Conversely, increased lipolysis during lack of insulin.

Growth hormone and growth hormone dependent synthesis og IGF-1 (Insulin-like growth factor -

1) is crucial for human growth before and during adolescence. As an adult GH and IGF-1 are still potent growth factors and also they exert essential regulatory properties on human metabolism(9,10) GH- signalling pathways go through the GH-receptor, which phosphorylates and thus activates the receptor associated Janus Kinase 2 (JAK2). The signals from this point have been examined in numerous studies. In rodents, the signal has been shown to run three ways (9,10) Studies on human fibroblast

cells have been able to support two of these pathways (MAPK - mitogen-activated protein

kinase and STAT - signal transducer and activator of transcription), but not through the

insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3-K) pathway. In human (in vivo) studies, GH stimulation and phosphorylation of STAT5 has been evident, however an association between GH stimulation and activation of MAPK and PI3-K has not been shown (11). The latter is interesting and remarkable, considering the insulin-agonistic and antagonistic effects of GH. GH stimulates lipolysis, but exactly how the lipolytic properties of GH are mediated is not fully understood. However, it is shown that GH has an effect on hormone-sensitive lipase (12) (HSL). Other options could be, as found in rodents, interaction via PI3-K signaling pathway or via G0S2/ATGL interaction, either directly or perhaps mediated through IGF-1. Humane intracellular signaling-pathways during development of ketosis/ketoacidosis are not well-known. The investigators believe that understanding these pathways and the exact mechanisms behind the development of ketoacidosis, is of great importance.


Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Male.


Inclusion Criteria: Diagnosis of Diabetes Mellitus Type I, C-peptide negative, 19 < BMI < 26, Written consent


Exclusion Criteria: Ischemic heart disease, Cardiac arrythmia, Epilepsy, Other medical illness


Locations and Contacts

Thomas Voss, MD, Phone: +45 29911146, Email: tsvo@ki.au.dk

Institute of Clinical Medicine, Aarhus, Aarhus C 8000, Denmark; Recruiting
Thomas Voss, MD, Phone: +45 29911146, Email: tsvo@ki.au.dk
Niels Møller, MD, Phone: +45 78462165, Email: nielsem@dadlnet.dk
Thomas Voss, MD, Principal Investigator
Additional Information

Related publications:

Bezaire V, Mairal A, Ribet C, Lefort C, Girousse A, Jocken J, Laurencikiene J, Anesia R, Rodriguez AM, Ryden M, Stenson BM, Dani C, Ailhaud G, Arner P, Langin D. Contribution of adipose triglyceride lipase and hormone-sensitive lipase to lipolysis in hMADS adipocytes. J Biol Chem. 2009 Jul 3;284(27):18282-91. doi: 10.1074/jbc.M109.008631. Epub 2009 May 11.

Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, Hoefler G, Zechner R. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 2006 May 5;312(5774):734-7.

Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Rydén M, Arner E, Sicard A, Jenkins CM, Viguerie N, van Harmelen V, Gross RW, Holm C, Arner P. Adipocyte lipases and defect of lipolysis in human obesity. Diabetes. 2005 Nov;54(11):3190-7.

Schweiger M, Schreiber R, Haemmerle G, Lass A, Fledelius C, Jacobsen P, Tornqvist H, Zechner R, Zimmermann R. Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J Biol Chem. 2006 Dec 29;281(52):40236-41. Epub 2006 Oct 30.

Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004 Nov 19;306(5700):1383-6.

Yang X, Lu X, Lombès M, Rha GB, Chi YI, Guerin TM, Smart EJ, Liu J. The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab. 2010 Mar 3;11(3):194-205. doi: 10.1016/j.cmet.2010.02.003.

Nielsen TS, Vendelbo MH, Jessen N, Pedersen SB, Jørgensen JO, Lund S, Møller N. Fasting, but not exercise, increases adipose triglyceride lipase (ATGL) protein and reduces G(0)/G(1) switch gene 2 (G0S2) protein and mRNA content in human adipose tissue. J Clin Endocrinol Metab. 2011 Aug;96(8):E1293-7. doi: 10.1210/jc.2011-0149. Epub 2011 May 25.

Teunissen BE, Smeets PJ, Willemsen PH, De Windt LJ, Van der Vusse GJ, Van Bilsen M. Activation of PPARdelta inhibits cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts. Cardiovasc Res. 2007 Aug 1;75(3):519-29. Epub 2007 May 3.

Birzniece V, Sata A, Ho KK. Growth hormone receptor modulators. Rev Endocr Metab Disord. 2009 Jun;10(2):145-56. doi: 10.1007/s11154-008-9089-x. Review.

Møller N, Jørgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009 Apr;30(2):152-77. doi: 10.1210/er.2008-0027. Epub 2009 Feb 24. Review.

Silva CM, Kloth MT, Whatmore AJ, Freeth JS, Anderson N, Laughlin KK, Huynh T, Woodall AJ, Clayton PE. GH and epidermal growth factor signaling in normal and Laron syndrome fibroblasts. Endocrinology. 2002 Jul;143(7):2610-7.

Beauville M, Harant I, Crampes F, Riviere D, Tauber MT, Tauber JP, Garrigues M. Effect of long-term rhGH administration in GH-deficient adults on fat cell epinephrine response. Am J Physiol. 1992 Sep;263(3 Pt 1):E467-72.

Starting date: May 2014
Last updated: October 15, 2014

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